Recently, the single nucleotide polymorphism (SNP) identified as rs1260326, in the glucokinase regulatory protein (GCKR), was associated with hypertriglyceridemia in adults. Because accumulation of triglycerides in hepatocytes represents the hallmark of steatosis, we aimed to investigate whether this variant might be associated with fatty liver (hepatic fat content, HFF%). Moreover, because recently rs738409 in thePNPLA3and rs2854116 in theAPOC3were associated with fatty liver, we explored how theGCKRSNP and these two variants jointly influence hepatosteatosis. We studied 455 obese children and adolescents (181 Caucasians, 139 African Americans, and 135 Hispanics). All underwent an oral glucose tolerance test and fasting lipoprotein subclasses measurement by proton nuclear magnetic resonance. A subset of 142 children underwent a fast gradient magnetic resonance imaging to measure the HFF%. The rs1260326 was associated with elevated triglycerides (CaucasiansP= 0.00014; African AmericansP= 0.00417), large very low-density lipoprotein (VLDL) (CaucasiansP= 0.001; African Americans,P= 0.03), and with fatty liver (CaucasiansP= 0.034; African AmericansP= 0.00002; and HispanicsP= 0.016). ThePNPLA3, but not theAPOC3rs2854116 SNP, was associated with fatty liver but not with triglyceride levels. There was a joint effect between thePNPLA3andGCKRSNPs, explaining 32% of HFF% variance in Caucasians (P= 0.00161), 39.0% in African Americans (P= 0.00000496), and 15% in Hispanics (P= 0.00342).Conclusion:
The rs1260326 inGCKRis associated with hepatic fat accumulation along with large VLDL and triglyceride levels.GCKRandPNPLA3act together to convey susceptibility to fatty liver in obese youths.